Although pain is a crucially important physiological response, it also results in unnecessary suffering and agony. The control and relief of pain is an important branch of medicine. Pain may come about both as a result of disease as well as a result of medical treatment such as chemotherapy. In either case, it is important to alleviate the pain as much as possible so as to enable the sufferer to function normally.
Two neural pathways relating to pain act concurrently in the body: (1) a sensory pathway which senses tissue damage and subsequently produces a feeling of pain; (2) an analgesic pathway which reduces the feeling of pain and prevents the flow of information about the pain to the central nervous system (CNS), thus allowing the organism to maintain ifs normal activity in spite of an injury. Anesthesia can be realized either by use of a drug which inhibits peripheral nerves that act as pain sensors or by enhancement of the natural analgesic system. Since these are different pathways, they are affected by different substances. For example, aspirin and lidocaine are active on the peripheral sensory pathway, while morphine and related substances are active on the analgesic system.
The most efficient analgesics currently in use are morphine-related substances of opiatic origin. It's well known that the brain makes a variety of endogenic opiates, and this explains the powerful effect of these substances. Their action on neurons is mediated by specialized receptors. Signals regulated by these receptors prevent the flow of information from the peripheral pain neurons to the CNS. These CNS neurons are also sensitive to a variety of other chemical substances including catecholamines (serotonin, noradrenalin etc.), neuroactive peptides (neurotensin) and inhibitory amino acids (glycin and GABA).
U.S. Pat. No. 4,619,916 to Di Stazio discloses 13 new tripeptides of the formula pGLU-X-TRP, where pGLU is cyclized glutamic acid (pyroglutamic acid) and X may be GLY, VAL, GLU, ASP, SER, ALA, ASN, GLN, ILE, LEU, PRO, LYS and ARG. Also disclosed are a process for their preparation, pharmaceutical formulations containing them for oral or parenteral administration and their use as hypotensive and analgesic agents. Further disclosed are lower alkyl esters of the tryptophan residue, in particular methyl or ethyl esters, for use as protecting groups in the production of the peptides. The protecting groups are removed at the completion of the synthesis process. There is no disclosure of a topical formulation.
WO 92/19254 discloses α-substituted mono, di, tri, tetra and pentapeptides useful in treating obesity, anxiety, gastrointestinal ulcers, pain, stroke and inflammation. Peptides of the formula pGLU-X-TRP are not disclosed.
The following tetrapeptides of the formula pGLU-X-TRP-Z appear in the literature:
X=L-Ala; Z=L-LeuOH, L-LeuOCH3, L-LeuNH2, L-MetOH, L-MetOCH3, or L-MetNH2 (DE 3,340,208);
X=Lys; Z=L-AlaOH or L-ProOH (Freer, R. J. and Stewart, J. M. (1971) Cienc. Cult. 23(4):539–42; Francis, B. and Kaiser, I. I. (1993) Toxicon 31(7):889–899);
X=L-Pro; Z=L-ValNH2, L-MetOH, L-MetOCH3, L-MetNH2 L-MetsulfoxideOH, L-MetsulfoxideOCH3, or L-MetsulfoxideNH2 (DE 3,340,208).